Neuropathic pain is a type of pain caused by damage to the central nervous or the peripheral nervous and includes symptoms such as a hyperalgesic response in which the threshold to spontaneous pain or invasive stimulation is decreased, and mechanical allodynia in which non-invasive mechanical stimulation or tactile stimulation which does not usually cause pain is mistakenly perceived as severe pain. Neuropathic pain, particularly allodynia is characterized in that intractable burning pain or stabbing pain lasts continuously for a long time and causes a decrease in the effectiveness of rehabilitation due to pain or the like, and is a pathological condition that significantly decreases the QOL of patients. It can be said that there is almost no satisfactory drug therapy for neuropathic pain and the development of a drug that satisfies both efficacy and safety for neuropathic pain has been demanded. However, the development of such a drug has not progressed as it should have. One of the reasons for this is considered to be that the mechanism of pathogenesis is not single and several mechanisms are intricately involved in the onset of the disease. The detailed pathogenic mechanisms of allodynia have not been elucidated yet, however, involvement of abnormal neuronal circuit formation due to an organic change and a functional change in neurons in the pain transmission pathway including nociceptive neurons has been proposed recently. Here, as the organic change, a phenomenon in which Aβ fibers terminating in laminae III-V of the spinal cord dorsal horn elongate its sprout axon into lamina II of the spinal cord dorsal horn which is the center of the pain transmission called substantia gelatinosa after a nerve injury can be exemplified. As the functional change, a phenomenon in which Aβ fibers presynaptically activate C fibers via interneurons, and the like can be exemplified (Non-patent document 1). Further, as a new factor for inducing abnormal neuronal circuit formation, involvement of expression of a guidance molecule which guides nerve fibers to a specific site and of release of a neuronal activator such as BDGF (brain-derived growth factor) or the like which is an allodynia enhancing factor accompanying the activation of spinal microglia has been proposed (Non-patent document 2).
As pathological conditions exhibiting neuropathic pain, diseases caused by central nervous disorders and peripheral nervous disorders are known. Examples of the central nervous disease include brain disorders, multiple sclerosis, and spinal cord injuries, and examples of the peripheral nervous disease include diabetes and herpes zoster.
In the current treatment of neuropathic pain, nonsteroidal antiinflammatory drugs (NSAIDs), opioid analgesics, and analgesic adjuvants (such as an NMDA receptor antagonist, an antidepressant, an antiarrhythmic, an anticonvulsant, or an antispasmodic) are used, however, neuropathic pain is resistant to therapy using NSAIDs and opioid analgesics, and it is very difficult to control with medication. Further, other than NSAIDs and opioid analgesics, as the analgesic adjuvant, an antidepressant (such as a tricyclic type, a tetracyclic type, an SSRI (a selective serotonin reuptake inhibitor), or an SNRI (a selective serotonin-noradrenaline reuptake inhibitor)), an anticonvulsant (such as carbamazepine), an antispasmodic (baclofen), an antiarrhythmic (such as lidocaine), an NMDA receptor antagonist (such as ketamine), a steroid (such as betamethasone), a therapeutic agent for pain based on the activation of a descending pain inhibitory system (Neurotropin, a formulation containing an extract isolated from the inflamed skin of rabbits inoculated with a vaccinia virus which is approved as a therapeutic agent for postherpetic neuralgia and the like), or the like is used (Non-patent document 3). However, the current situation is that these medicinal agents for improving peripheral pain have strong adverse reactions, and the medicinal agents for central pain have a low efficacy, and therefore, the development of a medicinal agent having a more stable and higher therapeutic effectiveness has been demanded.
On the other hand, in the central nervous system, a proteoglycan is considered to exert an activity of regulating various neuronal functions such as an axon guidance function by binding to various growth factors, cell adhesion factors, and so on (Non-patent documents 4 and 5). In central nervous diseases such as a spinal cord injury, it is known that a proteoglycan having chondroitin sulfate side chain is a neuronal axonal regeneration inhibitory factor which forms a glial scar in an injured area thereof. It has been reported that chondroitinase ABC, which is an enzyme capable of degrading chondroitin sulfate, dermatan sulfate (also referred to as chondroitin sulfate B), and the like forming a side chain of a proteoglycan, degrades a chondroitin sulfate side chain (including a dermatan sulfate side chain, hereinafter, the same shall apply) of a proteoglycan expressed in a glial scar in a spinal cord injury rat model and has an activity of improving a hind limb motor function (Non-patent document 8). It is considered that the neuronal axonal regeneration inhibitory activity of a chondroitin sulfate proteoglycan is exhibited mainly through an activation of Rho kinase (Non-patent document 6). On the other hand, it has been reported that ATP known as a pain substance strongly activates spinal microglia and causes an increase in the production of various mediators which promote abnormal neuronal circuit formation, synaptic trafficking accompanied by cytoskeletal reconstruction, or a release of a neurotransmitter and is involved in neuropathic pain. ATP activates also Rac which is a member of the Rho family (Non-patent document 7).
Further, it has been revealed that spinal microglia of the spinal cord dorsal horn are activated by a nerve injury, and stimulation of P2X4 receptors strongly expressed there causes neuropathic pain, and it has been proposed that the Rho kinase signal transduction pathway is involved as one of the pathways of these activation cascades (Non-patent document 7).
The efficacy of a chondroitinase in the treatment of a motor function for an injury of the central nervous system has been supported not only by, for example, Non-patent document 8, but also by Patent document 1 and the like. However, the efficacy as described in these documents means or intends that a function (such as a motor function) or a sensation which is lost by a nervous disorder is restored or recovered by degrading a chondroitin sulfate side chain of a proteoglycan and promoting the regeneration of injured neuronal axons or the like, and there is no reported case of an improving activity of a chondroitinase for pain caused by a nervous disorder as far as the present inventors have known. It is considered that it cannot be said that there is not at all an association between a recovery effect on a motor function or the like and an effect on neuropathic pain, however, at least there is no technical common knowledge that if there is a recovery effect on a motor function or the like, an improving effect on neuropathic pain is exhibited or can be expected. In fact, Bradbury, E. J. et al. confirmed a recovery efficacy of a chondroitinase on a motor function in a spinal cord injury rat model, however, they have reported that a recovery efficacy on a sensory function was not obtained (Non-patent document 8). Further, in the study of abnormal pain of human patients with a spinal cord injury (Non-patent document 9), an association between the level of residual motor ability and the presence or absence of abnormal pain such as allodynia is not observed, and therefore, the recovery of a motor function is not associated with the recovery of neuropathic pain.
On the other hand, it is known that abnormal elongation of primary afferent nerves adversely affect the function of nociceptive neurons and can lead to abnormal hypersensitivity to pain stimulations. Barritt, A. W. et al. studied the possibility in which the plasticity induced by a treatment with chondroitinase ABC after a spinal cord injury (a lumbar spinal injury) has adverse reactions. As a result of the study, they confirmed that the elongation of primary afferent nerves was observed, but connectivity of nociceptive neurons or development of mechanical allodynia or thermal hyperalgesia was not observed by the treatment (Non-patent document 10).
Accordingly, it has not been known so far that a chondroitinase has an activity of improving neuropathic pain.
Patent document 1: JP-T-2005-526740 (WO 2003/074080)
Non-patent document 1: MINAMI Toshiaki, et al., “Plasticity of pain”, Seibutsu Butsuri, 41(1), 15-19 (2001)
Non-patent document 2: TSUDA Makoto, “A new mechanism of neuropathic pain through ATP receptors in spinal microglia”, Folia Pharmacologica Japonica, 129, 349-353 (2007)
Non-patent document 3: ISEKI Masako et al., “Current clinical status of and future expectations for pain alleviation agents”, Folia Pharmacologica Japonica, 128, 326-329 (2006)
Non-patent document 4: Crespo, D. et al., 2007, How does chondroitinase promote functional recovery in the damaged CNS?, Experimental Neurology 206 (2), 159-71
Non-patent document 5: Wit, J. D. et al., 2007, Semaphorins: Receptor and Intracellular Signaling Mechanisms, Chapter 7, Proteoglycans as Modulators of Axon Guidance Cue Function, 73-89
Non-patent document 6: Monnier, P. P. et al., 2003, The Rho/ROCK pathway mediates neurite growth-inhibitory activity associated with the chondroitin sulfate proteoglycans of the CNS glial scar, Mol. Cell. Neurosci. 22, 319-330
Non-patent document 7: Honda, S. et al., 2001, Extracellular ATP or ADP Induce Chemotaxis of Cultured Microglia through Gi/o-Coupled P2Y Receptors, J. Neurosci. 21(6), 1975-1982
Non-patent document 8: Bradbury, E. J. et al., 2002, Chondroitinase ABC promotes functional recovery after spinal cord injury, Nature 416, 636-640
Non-patent document 9: Specified Non-profit Corporation, JAPAN SPINAL CORD FOUNDATION (JSCF), Fact-finding report publication about abnormal sharp pain with the SCI), September, 2004,
Non-patent document 10: Barritt, A. W. et al., 2006, Chondroitinase ABC promotes sprouting of intact and injured spinal systems after spinal cord injury, Journal of Neuroscience 26(42), 10856-10867